Action Points

Note that a letter published in the New England Journal of Medicine suggests that the statin-comparator arm of a trial evaluating a PCSK9 inhibitor was inadequately managed.

Be aware that the original study authors note that the frequency of high-dose statin use in the control arm was similar to that seen in population-based studies.

Suboptimal high-dose statin use for the high-risk individuals treated in the placebo arms of a key alirocumab (Praluent) trial might have biased the findings, one group suggested, while another pointed out possible bias in side effect profiles in evolocumab trials.

That trial spurred hope for a possible halving of cardiovascular events with the PCSK9 inhibitor alirocumab based on a post hoc analysis of 78-week follow-up, along with an analysis of the open-label OSLER extension studies with evolocumab (Repatha) showing a similar association of lower cardiovascular event risk with that anti-PCSK9 monoclonal antibody.

Participants in the alirocumab trial had heterozygous familial hypercholesterolemia, established coronary heart disease, or a coronary heart disease risk equivalent. Whereas current guidelines would suggest high-intensity statin treatment for most such patients, only 47% of those in the study actually got high-dose statins, Auer's group pointed out.

"Treatment with high-dose statins would have brought a much higher percentage of patients in the placebo group to the goal of an LDL cholesterol level of less than 70 mg/dL," they wrote. "In addition, appropriate use of high-dose statins would have been associated with a lower rate of major adverse cardiovascular events in the placebo group."

However, the situation isn't worse than in current practice, with only a quarter of U.S. high-risk patients getting a high-intensity statin and less than 10% getting one in Europe, responded ODYSSEY LONG TERM authors Jennifer Robinson, MD, MPH, of the University of Iowa in Iowa City, and John J.P. Kastelein, MD, PhD, of the Academic Medical Center Amsterdam.

"This factor brings to light the need for wider implementation of guidelines on the basis of evidence from randomized trials, which have clearly shown that high-intensity statins reduce the rate of cardiovascular events more than moderate-intensity statins," they wrote in NEJM.

They pointed out that the trial protocol allowed lower statin doses for "documented safety or adverse-event issues (e.g., previous muscle symptoms or creatine kinase elevations during receipt of a high-dose statin, which accounted for 17% of study patients) or because of regional practices or local labeling (which accounted for 28% of study patients)."

A second letter to the NEJM editors argued about "methodologic particularities" of the OSLER 1 and 2 extension studies.

"All patients had to be continuously enrolled in one of 12 parent studies," Iuri M. Goemann, MD, of Hospital de Clinicas de Porto Alegre, Brazil, and colleagues wrote. "As a consequence, it is reasonable to wonder whether the resulting population constitutes a group that is biased on the basis of side-effect profile by the parent studies."

The parent trials that fed patients in to those extension studies had non-trivial adverse rates, they pointed out:

8% in the GAUSS-2 trial discontinued evolocumab due to adverse event

5.5% of participants in the DESCARTES trial had a serious adverse event on the drug

5% of evolocumab patients in the RUTHERFORD-2 trial had muscle-related adverse events, compared with 1% on placebo

"Moreover, the still unpublished results of the THOMAS-1 and THOMAS-2 trials leave us with incomplete information with respect to adverse events," Goemann's group noted. "This bias critically limits the validity of the OSLER results for adverse events. The potential benefits from the phenomenal reduction in LDL cholesterol induced by evolocumab should be carefully balanced against its unknown long-term safety profile."

"However, it should be noted that the majority of the patients who did not enter our study stated their intention not to do so at the start of the parent trial owing to the time commitment or other personal reasons," countered the OSLER extension study authors.

Goemann's selectively cited data from just a few of the 12 parent trials, Marc S. Sabatine, MD, MPH, of Brigham and Women's Hospital in Boston, and colleagues pointed out.

"What may be more helpful are the data from a comprehensive pooled analysis of the blinded, controlled parent trials, which show that the rates of adverse events leading to study-drug discontinuation were 2.2% in the control groups and 1.9% in the evolocumab groups, findings that support the acceptable side-effect profile of the drug," they wrote.

Both groups of investigators noted that the final word will have to come from the ongoing large cardiovascular endpoint trials.

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